My laboratory is interested in the mechanisms of biological timing and in particular intrinsic daily or circadian clocks. The dominant circadian clock in mammals is localised to the suprachiasmatic nuclei (SCN) in the brain. This clock and its synchronisation to the external world by light and other stimuli regulates daily rhythms in sleeping, feeding, and cognition. Many brain cells or neurones here contain the intracellular molecular clock of which the period and cryptochrome genes are key components. A key property of SCN neurones is that they are spontaneously active, generating circadian variation in the production of action potentials, even when isolated in vitro. Surprisingly, the precise relationship between the intracellular molecular clock and the membrane properties of SCN neurons is unclear. It is known though that the coordinated activity of these SCN cell autonomous clocks is achieved through intercellular signalling with neuropeptides and other neurotransmitters. In mice lacking some of these neuropeptides, SCN molecular and neuronal activity is diminished and such animals can become behaviourally arrhythmic and show impaired synchronisation to the environmental light. Intriguingly, expression of these neuropeptides appears to decrease with age and this may underpin alterations in circadian function that accompany old age. Currently we have three main projects:
1) What is the relationship between the intracellular molecular clock and electrical activity of SCN neurons? For these studies we use whole-cell patch clamp recording approaches to measure electrical activity in SCN neurones from mice expressing fluorescent reporters of clock gene activity. We have identified that when period1 gene expression is high during the day, that some SCN neurones become very depolarised and surprisingly stop firing action potentials. At night, when period1 gene expression is low, these neurones become hyperpolarised and fire action potentials at low frequencies or not at all. We are currently investigating how clock gene mutations that alter the period or amplitude of the molecular clock affect SCN electrical activity. Interpretation of these electrophysiological investigations are complemented and guided by mathematical modelling of ion channels, intracellular signaling, and information flow in circadian circuits.
2) Can we fix a broken clock? In addition to light, the mammalian circadian system can be reset by stimuli that promote internal arousal. An example of this is scheduled physical exercise. We have found that scheduled exercise in a running-wheel for 6h a day promotes circadian rhythms in mice with a dysfunctional SCN clock. We are examining how exercise influences the molecular clock in the SCN and the coordination of the SCN clock with peripheral oscillators. Circadian control of behaviour and physiology can deteriorate with age, and we are assessing whether the running-wheel regimen can improve daily rhythms in aged mice. Further, since exercise is also beneficial for cognition, we are investigating whether restoration of circadian rhythms by daily exercise is accompanied by improvements in learning and memory.
3) Do neurons in other areas of the brain have SCN-like properties? Core clock gene expression is not limited to the SCN and is detected in several other brain sites. One such area is the habenula, a structure in the epithalamus that is implicated in the regulation of several important processes including circadian rhythms in behaviour. Using a bioluminenscent reporter of the PER2 protein, we have localised rhythmic PER2 expression to the habenula, suggesting that the habenula neurones have intrinsic circadian rhythm generating characteristics.